An autoimmune disease results from an inappropriate immune response directed against a self antigen (an autoantigen), which is a deviation from the normal state of self-tolerance. Self-tolerance arises when the production of T cells and B cells capable of reacting against autoantigens has been prevented by events that occur in the development of the immune system during early life. The cell surface proteins that play a central role in regulation of immune responses through their ability to bind and present processed peptides to T cells are the major histocompatibility complex (MHC) molecules (Rothbard, J. B., et al., 1991, Annu. Rev. Immunol. 9:527).
A number of therapeutic agents have been developed to treat autoimmune diseases, including general anti-inflammatory drugs such as “super aspirins”, for example, agents that can prevent formation of low molecular weight inflammatory compounds by inhibiting a cyclooxygenase; agents that can function by inhibiting a protein mediator of inflammation, for example, by sequestering the inflammatory protein tumor necrosis factor (TNF) with an anti-TNT specific monoclonal antibody or antibody fragment, or with a soluble form of the TNF receptor; agents that target a protein on the surface of a T cell and generally prevent interaction with an antigen presenting cell (APC) by inhibiting the CD4 receptor or the cell adhesion receptor ICAM-1. However, compositions having natural folded proteins as therapeutic agents can incur problems in production, formulation, storage, and delivery. Several of these problems necessitate delivery to the patient in a hospital setting.
An additional target for inhibition of an autoimmune response is the set of lymphocyte surface proteins MHC molecules, particularly a protein encoded by an MHC class II gene, for example, HLA-DR, -DQ and -DP. Each of the MHC genes is found in a large number of alternative or allelic forms within a mammalian population. The genomes of subjects affected with certain autoimmune diseases, for example multiple sclerosis (MS) and rheumatoid arthritis (RA), are more likely to carry one or more characteristic MHC class II alleles, to which that disease is linked.
RA is a common human autoimmune disease with a prevalence of about 1% among Caucasians (Harris, E. J. et al., 1997, In Textbook of Rheumatology 898-932), currently affecting 2.5 million Americans. RA is characterized by chronic inflammation of the synovial joints and infiltration by activated T cells, macrophages and plasma cells, leading to a progressive destruction of the articular cartilage. It is the most severe form of joint disease. Inherited susceptibility to RA is strongly associated with the affected subject having at the MHC class II DRB1 locus the allele DRB1*0401, DRB1*0404, or DRB1*0405 or the DRB1*0101 allele. The nature of the autoantigen(s) in RA is poorly understood, although collagen type II (CII) is a prominent candidate. An immunodominant T cell epitope is collagen type II corresponding to residues 261-273 has been identified (Fugger, L., et al., 1996, Eur. J. Immunol. 26: 928-933).
It would be desirable to identify agents that were able to bind specifically to one or more of the linked MHC class II molecules and thereby to inhibit an inappropriate immune response. An agent that interacts and binds relatively nonspecifically to several MHC class II molecules is Copolymer 1 (Cop 1), a synthetic amino acid heteropolymer that was shown to be capable of suppressing experimental allergic encephalomyelitis (EAE; Sela, M., R. Arnon, et al., 1990, Bull. Inst. Pasteur (Paris)), which can be induced in the mouse and is a model for MS. Cop 1 which is poly(Y,E,A,K), indicated herein “YEAK” using the one letter amino acid code (see infra; Y represents tyrosine, E glutamic acid, A alanine, and K lysine) has been used to treat relapsing forms of MS but does not suppress the disease entirely (Bornstein, M. B., et al., 1987, N. Engl. J. Med. 317:408; Johnson, K P., et al., 1995, Neurology 45:1268). There is no suggestion that YEAK is an effective treatment for another autoimmune disease such as RA.
There is a need for improved treatments for autoimmune diseases. A potential source of such treatments would be to identify agents that bind selectively to a purified MHC class II allele protein molecule in vitro, particularly to a protein which is a product of an MHC class II allele that is associated with an autoimmune disease. In addition, the agent should also bind to that protein as it occurs on the surfaces of antigen presenting cells in vivo, and thereby can block, anergize, or inactivate T cells that are responsible for the autoimmune disease.